Aspirin and clopidogrel with or without phenprocoumon after drug eluting coronary stent placement in patients on chronic oral anticoagulation

Objectives. Optimal antithrombotic/anticoagulation therapy in patients on chronic oral anticoagulation (OAC) undergoing drug‐eluting stent (DES) implantation is unknown. We investigated the efficacy and safety of two regimens of antithrombotic/anticoagulation therapy in patients who present for DES implantation whilst on OAC. Methods. We included a series of 515 patients on OAC who underwent DES implantation between 2002 and 2007. Based on predefined clinical and echocardiographic criteria, 306 patients continued OAC (triple therapy) and 209 patients discontinued OAC (dual therapy) for the time they received antiplatelet therapy with clopidogrel and aspirin [stent‐related antithrombotic treatment (SRAT)]. The primary end point was a composite of death, myocardial infarction, stent thrombosis or stroke. Results. During SRAT the primary endpoint was observed in 13 patients in the group with triple therapy versus 15 patients in the group with dual therapy [Kaplan–Meier estimates 4.2% and 7.2%, odds ratio (OR) = 0.61, 95% confidence interval (CI) 0.29–1.28; P = 0.19]. At 2 years of follow‐up, the primary endpoint was observed in 35 patients in the group with triple therapy versus 36 patients in the group with dual therapy (Kaplan–Meier estimates 14.1% and 18.0%, OR = 0.76, 95% CI: 0.48–1.21; P = 0.25). Two‐year incidence of major bleeding was 1.4% (n = 4, triple therapy) versus 3.1% (n = 6, dual therapy) (P = 0.34). Conclusions. In patients on chronic OAC undergoing DES implantation, clinical and echocardiographic criteria help to define postprocedural antithrombotic/anticoagulation therapy. Based on these criteria, both a double antiplatelet therapy (clopidogrel plus aspirin) and a triple therapy (OAC plus clopidogrel plus aspirin) are associated with favourable safety and efficacy.     

Switching of Oral Anticoagulation Therapy After PCI in Patients With Atrial Fibrillation: The RE-DUAL PCI Trial Subanalysis

ObjectivesThe aim of this study was to assess if prior oral anticoagulant agent (OAC) use modifies the lower bleeding risk observed with dabigatran dual therapy (dabigatran twice daily plus a P2Y₁₂ inhibitor) versus warfarin triple therapy (warfarin plus a P2Y₁₂ inhibitor plus aspirin) in patients with atrial fibrillation who underwent percutaneous coronary intervention (PCI).BackgroundIn the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial, the primary outcome of major bleeding or clinically relevant nonmajor bleeding was lower with dabigatran dual therapy versus warfarin triple therapy in patients with atrial fibrillation who underwent PCI.MethodsA total of 2,725 patients were randomized to dual therapy with dabigatran (110 or 150 mg twice daily) plus clopidogrel or ticagrelor or triple therapy with warfarin plus aspirin and clopidogrel or ticagrelor. Subgroup analysis compared risk for major bleeding or clinically relevant nonmajor bleeding and a composite thromboembolic endpoint in patients with prior OAC use and in those who were OAC treatment naive.ResultsRisk for major bleeding or clinically relevant nonmajor bleeding was reduced with both dabigatran dual therapies compared with warfarin triple therapy in both the prior OAC use group (hazard ratios: 0.58 [95% confidence interval (CI): 0.42 to 0.81] and 0.61 [95% CI: 0.41 to 0.92] with 110 and 150 mg dabigatran, respectively) and the OAC-naive group (hazard ratios: 0.49 [95% CI: 0.38 to 0.63] and 0.76 [95% CI: 0.59 to 0.97] with 110 and 150 mg dabigatran) (p for interaction = 0.42 and 0.37, 110 and 150 mg dabigatran, respectively). The risk for thromboembolic events seemed similar with dabigatran dual therapy (both doses) and warfarin triple therapy across subgroups.ConclusionsBleeding risk was reduced with dabigatran dual therapy versus warfarin triple therapy in patients with atrial fibrillation after PCI, regardless of whether they were prior OAC users or OAC treatment naive. These results suggest that it is also safe to switch patients on OAC pre-PCI to dabigatran dual therapy post-PCI.     

Ticagrelor Versus Clopidogrel as Part of Dual or Triple Antithrombotic Therapy: a Systematic Review and Meta-Analysis

Purpose

Clopidogrel is the standard P2Y₁₂ receptor inhibitor used in patients requiring both antiplatelet therapy and oral anticoagulation (OAC). We investigated the safety and efficacy of ticagrelor as an alternative to clopidogrel in patients on OAC.

Methods

A systematic electronic literature search was performed in MEDLINE, EMBASE, and the Cochrane Library for randomised controlled studies that examined the relative safety and efficacy of clopidogrel versus ticagrelor among patients requiring therapy with antiplatelet agents plus OAC.

Results

Three randomised controlled trials were identified with a total of 5659 patients. The risk of clinically significant bleeding was significantly increased among patients on dual or triple antithrombotic therapy who received ticagrelor compared with patients on clopidogrel (OR 1.52, 95% CI 1.12 to 2.06, and OR 1.7, 95% CI 1.24 to 2.33, respectively). Among those on triple therapy, ticagrelor was associated with a significantly higher risk of major adverse cardiovascular events (MACE) compared to clopidogrel (OR 1.88, 95% CI 1.26 to 2.80). Patients who received dual therapy exhibited similar risk of MACE and stroke with ticagrelor versus clopidogrel (OR 1.14, 95% CI 0.83 to 1.56, and OR 0.42, 95% CI 0.10 to 1.74, respectively).

Conclusion

The use of ticagrelor as part of dual or triple antithrombotic therapy is associated with significantly higher rates of clinically relevant haemorrhagic complications compared with clopidogrel. Among triple therapy-treated patients, the use of ticagrelor might increase thromboembolic and ischaemic cardiac events.

     

Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis.

OBJECTIVES: We evaluated safety and efficacy of triple antiplatelet therapy with aspirin, clopidogrel, or ticlopidine and cilostazol after coronary stenting. BACKGROUND: Triple antiplatelet therapy might have beneficial effect to prevent thrombotic complications in patients undergoing coronary stenting. METHODS: Patients undergoing successful coronary stenting were divided into dual antiplatelet therapy (aspirin plus clopidogrel or ticlopidine, group I, n = 1,597) and triple antiplatelet therapy (aspirin plus clopidogrel or ticlopidine plus cilostazol, group II, n = 1,415) groups. The primary end point included death, myocardial infarction, target lesion revascularization, or stent thrombosis within 30 days. The secondary end point was side effects of study drugs, including major bleeding, vascular complication, hepatic dysfunction, and hematological complications. RESULTS: Multi-vessel stenting and the use of long stents were more prevalent in group II than in group I. The primary end point was 0.8% in group I and 0.3% in group II (p = 0.085). Stent thrombosis within 30 days was significantly lower in group II (n = 1, 0.1%) than in group I (n = 9, 0.5%; p = 0.024). The independent predictors of stent thrombosis were primary stenting (odds ratio [OR] 7.9, 95% confidence interval [CI] 2.0 to 30.8, p = 0.003) and triple therapy (OR 0.12, 95% CI 0.015 to 0.98, p = 0.048). The overall adverse drug effects, including major bleeding, neutropenia, and thrombocytopenia, were no different between two groups (1.8% vs. 2.6%, p = 0.104). CONCLUSIONS: Compared with the dual antiplatelet regimen, triple antiplatelet therapy seemed to be more effective in preventing thrombotic complications after stenting without an increased risk of side effects. Triple antiplatelet therapy might be safely applied in patients or lesions with a high risk of stent thrombosis.     

Periprocedural Management and In-Hospital Outcome of Patients with Indication for Oral Anticoagulation Undergoing Coronary Artery Stenting

Purpose: In patients on oral anticoagulation (OAC) undergoing coronary stenting (PCI-S), procedural management and in-hospital outcome have never been specifically and prospectively investigated. Also, the contribution of early bleeding to the relevant hemorrhagic rate reported at follow-up with triple therapy of OAC, aspirin, and clopidogrel is largely unknown.
Methods: Consecutive patients with indication for OAC undergoing PCI-S at 5 centers were enrolled and prospectively evaluated.
Results: Out of 3410 patients undergoing PCI-S in the study period, indication for OAC was present in 4.8%. Femoral approach and bare metal stents were the most frequently used. During PCI-S, OAC was continued in about 30% of patients, whereas in about 20% heparin bridging was carried out. Glycoprotein IIb/IIIa inhibitors were rarely used (11%), whereas a standard bolus of unfractionated heparin was given in 93% of cases. Major adverse cardiovascular events (MACE) occurred in 4.8% of patients and major bleeding in 4.3%. No predictors of MACE or bleeding were identified, although the femoral approach was of borderline significance for major bleeding (OR 4.6, 95% CI 1.0–20.8; P = 0.05). A history of previous hemorrhage (OR 5.3, 95% CI 1.6–18.1; P = 0.007) predicted Carbofilm™-coated stent implantation.
Conclusions: A limited, albeit clinically relevant, proportion of patients undergoing PCI-S has indication for OAC. Procedural management appears not substantially different from that of common patients. In-hospital major bleeding is relevant and should be taken into account when evaluating the overall hemorrhagic rate at a medium- to long-term follow-up.     

Impact of abciximab on mortality and reinfarction in patients with acute ST‐segment elevation myocardial infarction treated with primary stenting

Objectives: To combine data from all randomized trials of abciximab versus placebo or open‐label control in patients with STEMI treated with primary stenting to assess the short‐term and long‐term mortality, reinfarction, and bleeding complications. Background: Clinical trials of adjunctive abciximab therapy in patients with ST‐segment elevation myocardial infarction (STEMI) undergoing primary stenting have produced conflicting results. Methods: Formal searches of electronic databases (Medline, Cochrane) from January 1990 to April 2009 were performed. Five trials randomizing 2,937 patients (1,475 in the abciximab group, 1,462 in the placebo group) were included in the analysis. Results: When compared with placebo, abciximab was not associated with a significant reduction in the odds of 30‐day (OR 0.71, 95% CI: 0.45–1.14, P = 0.16) or long‐term (OR 0.85, 95% CI: 0.48–1.50, P = 0.57) mortality. Similarly, the rate of reinfarction was not statistically different at 30 days (OR 0.59, 95% CI: 0.30–1.17, P = 0.13) or at long‐term follow‐up (OR 0.67; 95% CI: 0.39–1.16, P = 0.16). However, when trials with upstream use of thienopyridines were excluded, abciximab was associated with a significant reduction in the composite of death or reinfarction at 30 days (OR 0.45; 95% CI: 0.26–0.77, P = 0.004) but not at long‐term follow‐up (OR 0.59; 95% CI: 0.27–1.28, P = 0.18). Conclusion: Routine use of abciximab in patients with STEMI treated with primary stenting may reduce short‐term rates of death or reinfarction in patients not administered preprocedural thienopyridine therapy, but does not appear to be beneficial in those who receive preprocedural thienopyridines. © 2009 Wiley‐Liss, Inc.     

The effectiveness and safety of triple-antiplatelet treatment based on cilostazol for patients receiving percutaneous coronary intervention: a meta-analysis

The combination of cilostazol, aspirin, and clopidogrel (triple therapy) after percutaneous coronary intervention has been considered as an alternative therapy. We performed a meta-analysis based on 8 randomized controlled trials with a total of 3332 patients to compare the effectiveness and safety of this triple therapy with traditional dual therapy (aspirin and clopidogrel). Our findings suggested that the triple therapy is more effective than dual therapy in preventing restenosis (odds ratio [OR]: 0.52, 95% confidence interval [CI]: 0.40-0.66, P < 0.00001), maintaining minimal lumen diameter (OR: 0.15, 95% CI: 0.10-0.20, P < 0.00001), and avoiding target-vessel revascularization (OR: 0.62, 95% CI: 0.47-0.82, P = 0.001). There is also no significant difference in major adverse cardiac and cerebrovascular events between the 2 therapies, except the smaller occurrence rate of target-lesion revascularization in the triple-therapy group (OR: 0.42, 95% CI: 0.26-0.69, P = 0.0005). However, the triple therapy is associated with a higher level of adverse drug events, including rash (OR: 2.45, 95% CI: 1.41-4.23, P = 0.001), gastrointestinal disorders (OR: 2.59, 95% CI: 1.26-5.30, P = 0.009), and drug discontinuation (OR: 3.80, 95% CI: 1.59-9.10, P = 0.003), but it has no difference in bleeding compared with the dual therapy (OR: 1.05, 95% CI: 0.71-1.55, P = 0.80). Additional Supporting Information may be found in the online version of this article. Ping Wang, MS and Shijie Zhou, MS contributed equally to this article. The authors have no funding, financial relationships, or conflicts of interest to disclose.     

Prognostic implications of early and long-term bleeding events in patients on one-year dual antiplatelet therapy following drug-eluting stent implantation

Background : Bleeding has emerged as a predictor of early and late mortality after percutaneous coronary interventions. However, the prevalence and predictors of long‐term bleeding events in patients on prolonged dual antiplatelet therapy (DAPT) after drug‐eluting stent (DES) implantation has been poorly explored. Methods : A total of 1,437 patients undergoing DES implantation discharged on DAPT with aspirin and clopidogrel for 1 year were studied. Patients were followed for up to 4 years (34.3 ± 14.4 months) and the prevalence and predictors of in‐hospital and long‐term thrombolysis in myocardial infarction (TIMI) major and minor bleeding events evaluated. The impact of bleeding events on major adverse cardiac events (MACE), overall death, and stent thrombosis (ST) was also assessed. Results : The incidences of 30 days major and minor bleeding were 1.3 and 3.3%, respectively. The incidences of 1‐year major and minor bleeding were 3.0 and 5.6%, respectively. The incidences of major and minor bleeding up to 4‐year follow‐up were 3.6 and 6.9%, respectively. At multivariable analysis, 1‐year major bleeding was positively predicted by use of oral anticoagulants at hospital discharge [odds ratio (OR) = 13.4, 95% confidence interval (CI) 3.0–59.2, P = 0.001], anemia at admission (OR = 6.7, 95% CI = 2.7–16.5, P < 0.001) and use of glycoprotein IIb/IIIa inhibitors (OR = 2.7, 95% CI = 1.1–6.5, P = 0.03) and negatively predicted by male gender (OR = 0.39, 95% CI = 0.16–0.97, P = 0.042). Overall, major bleeding at 1 year and at long‐term follow‐up was associated with an increased risk of MACE, cardiac death and ST. Patients who had any bleeding event were more likely to prematurely discontinue antiplatelet therapy (50% vs. 9.6%, P < 0.001). Conclusions : In DES‐treated patients on prolonged DAPT, major bleeding occurring at 1 year and up to 4 years following DES implantation in patients on prolonged DAPT is associated with poor long‐term prognosis. © 2012 Wiley Periodicals, Inc.     

Risk of Bleeding on Triple Antithrombotic Therapy After Percutaneous Coronary Intervention/Stenting: A Systematic Review and Meta-analysis

Background

There are no reported randomized controlled trials of triple antithrombotic therapy (TT; aspirin plus a thienopyridine plus vitamin K antagonist) vs dual antiplatelet therapy (DAPT; aspirin plus a thienopyridine) among patients undergoing percutaneous coronary intervention with stenting (PCI-S). A systematic review and meta-analysis was undertaken to assess the risk of bleeding among patients receiving TT after PCI-S.

Methods

Electronic databases were searched for studies reporting bleeding among patients receiving TT after PCI-S. Of the 4108 articles screened, 18 met study inclusion criteria and underwent detailed data extraction: of these, 6 reported in-hospital outcomes, 14 reported 30-day outcomes, and 9 reported 6-month outcomes. At each time point, pooled estimates of bleeding with TT were ascertained and where possible summary odds ratios (ORs) for comparative risks vs DAPT were calculated.

Results

The pooled estimate of major bleeding rate with TT post PCI-S was 2.38% by 30 days postprocedure (95% confidence interval [CI], 0.98-3.77%) and 4.55% by 6 months postdischarge (95% CI, 0.56-8.53%). At 30 days and 6 months the rates of major bleeding with TT were significantly higher than those observed with DAPT: OR, 2.38 at 30 days (95% CI, 1.05-5.38) and OR, 2.87 at 6 months (95% CI, 1.47-5.62).

Conclusions

This systematic review and meta-analysis of reports of triple therapy with a vitamin K antagonist, aspirin, and clopidogrel after PCI-S provides precise and valid bleeding risk data. Based on existing observational studies the rates of major and any bleeding associated with TT are clinically important and significantly greater than those reported with DAPT.     

Patients with peripheral arterial disease in the CHARISMA trial

Aims: The aim of this study was to determine whether clopidogrel plusaspirin provides greater protection against major cardiovascularevents than aspirin alone in patients with peripheral arterialdisease (PAD). Methods and results: This is a post hoc analysis of the 3096 patients with symptomatic(2838) or asymptomatic (258) PAD from the CHARISMA trial. Therate of cardiovascular death, myocardial infarction (MI), orstroke (primary endpoint) was higher in patients with PAD thanin those without PAD: 8.2% vs. 6.8% [hazard ratio (HR), 1.25;95% CI 1.08, 1.44; P = 0.002]. Among the patients with PAD,the primary endpoint occurred in 7.6% in the clopidogrel plusaspirin group and 8.9% in the placebo plus aspirin group (HR,0.85; 95% CI, 0.66–1.08; P = 0.18). In these patients,the rate of MI was lower in the dual antiplatelet arm than theaspirin alone arm: 2.3% vs. 3.7% (HR, 0.63; 95% CI, 0.42–0.96;P = 0.029), as was the rate of hospitalization for ischaemicevents: 16.5% vs. 20.1% (HR, 0.81; 95% CI, 0.68–0.95;P = 0.011). The rates of severe, fatal, or moderate bleedingdid not differ between the groups, whereas minor bleeding wasincreased with clopidogrel: 34.4% vs. 20.8% (odds ratio, 1.99;95% CI, 1.69–2.34; P < 0.001). Conclusion: Dual therapy provided some benefit over aspirin alone in PADpatients for the rate of MI and the rate of hospitalizationfor ischaemic events, at the cost of an increase in minor bleeding.     

Dabigatran Dual Therapy Versus Warfarin Triple Therapy Post–PCI in Patients With Atrial Fibrillation and Diabetes

ObjectivesThe aim of this study was to evaluate dabigatran dual therapy versus warfarin triple therapy in patients with or without diabetes mellitus in the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial.BackgroundIt is unclear whether dual therapy is as safe and efficacious as triple therapy in patients with atrial fibrillation with diabetes following percutaneous coronary intervention.MethodsIn RE-DUAL PCI, 2,725 patients with atrial fibrillation (993 with diabetes) who had undergone PCI were assigned to warfarin triple therapy (warfarin, clopidogrel or ticagrelor, and aspirin) or dabigatran dual therapy (dabigatran 110 mg or 150 mg twice daily and clopidogrel or ticagrelor). Median follow-up was 13 months. The primary outcome was the composite of major bleeding or clinically relevant nonmajor bleeding, and the main efficacy outcome was the composite of death, thromboembolic events, or unplanned revascularization.ResultsAmong patients with diabetes, the incidence of major bleeding or clinically relevant nonmajor bleeding was 15.2% in the dabigatran 110 mg dual therapy group versus 27.5% in the warfarin triple therapy group (hazard ratio [HR]: 0.48; 95% confidence interval [CI] 0.35 to 0.67) and 23.8% in the dabigatran 150 mg dual therapy group versus 25.1% in the warfarin triple therapy group (HR: 0.87; 95% CI: 0.62 to 1.22). Risk for major bleeding or clinically relevant nonmajor bleeding was also reduced with both dabigatran doses among patients without diabetes (dabigatran 110 mg dual therapy: HR: 0.54; 95% CI: 0.42 to 0.70; dabigatran 150 mg dual therapy: HR: 0.63; 95% CI: 0.48 to 0.83). Risk for the efficacy endpoint was comparable between treatment groups for both patients with and those without diabetes. No interaction between treatment and diabetes subgroup could be observed, either for bleeding or for composite efficacy endpoints.ConclusionsIn this subgroup analysis, dabigatran dual therapy had a lower risk for bleeding and a comparable rate of the efficacy endpoint compared with warfarin triple therapy in patients with atrial fibrillation with or without diabetes following percutaneous coronary intervention.     

Early and late outcomes of clopidogrel and Coumadin combination for patients on oral anticoagulants undergoing coronary stenting

BackgroundIn patients under oral anticoagulant requiring percutaneous coronary intervention (PCI) with stent implantation, the optimal association between aspirin, clopidogrel and oral anticoagulant (OAC) remains cumberstome. Triple therapy and dual therapy using aspirin and OAC have been evaluated and are associated with a high frequency of major bleedings. The combination of clopidogrel and OAC has never been evaluated.ObjectiveWe aimed to investigate the safety and efficacy of clopidogrel and OAC in patients requiring OAC undergoing PCI for acute coronary syndrome.MethodsA monocenter retrospective study was undertaken between 2000 and 2006 and included all patients undergoing PCI with stent implantation on OAC. On discharge dual therapy with clopidogrel and OAC was prescribed. The primary end-point was the frequency of major TIMI bleedings. Secondary end-points were major cardiovascular event (MACE). Results are reported as rate of events with 95% confidence intervals (CI).ResultsTwo hundreds and nine patients were followed for 71 ± 22 months. The indication for oral anticoagulation was atrial fibrillation in 80% of patients, a valvular prothesis in 18% and a history of pulmonary embolism in 5%. The rate (95%CI) of major bleeding was 2.4% (0.9%-5.8%) 2.87% (1.17%-6.44%) and 3.8% (1.79%-7.68%) at 1 month, 12 months and 71 months respectively, which represent 8 events among which 2 were fatal. The MACE rate (95%CI) was low: 0% at one month, 3.8% (1.79%-7.68%) at 12 months and 24.4% (19.07%-30.65%) at 71 months of follow up. Only one stent thrombosis was recorded at the ninth month. The overall rate of death was 9.5% (6.28%-14.32%) among which 2.87% (1.17%-6.44%) were of cardiovascular origin.ConclusionThe use of clopidogrel and OAC combination in patients on OAC undergoing coronary stenting is safe and efficient at the short-term. At the long-term, this combination is probably not safe, with a relatively high incidence of fatal stroke.     

Long-term and short-term duration of thienopyridine therapy after coronary stenting in patients with chronic kidney disease a meta-analysis of literature studies

Abstract

The study aimed to compare the efficacy and safety outcome associated with a short and a prolonged duration of thienopyridine therapy in patients with chronic kidney disease (CKD) after coronary stenting. We systematically searched PubMed, EMBASE and the Cochrane Library from their inception to 1 January 2019 for studies comparing short and prolonged thienopyridine therapy in patients with CKD. Ischemic and bleeding events were considered as the clinical endpoints in this analysis. Odds Ratios (OR) with 95% confidence intervals (CIs) were used as estimates of effect size in random-effect models. Seven studies comprising a total of 17,628 CKD patients were included in the evaluation. Prolonged duration of thienopyridine use, when compared to short-term thienopyridine, was associated with reduced risk of all-cause mortality (odds ratio 0.75, 95% confidence interval: 0.70–0.81, P< .001) and stent thrombosis (OR: 0.54, 95% CI 0.32 to 0.89; P< .001), but the odds of myocardial infarction (OR: 0.91, 95% CI: 0.77–1.07; P = .23) and stroke (OR: 0.91, 95% CI 0.73 to 1.13; P = .38) did not differ according to different duration of thienopyridine. As for bleeding events, long-term thienopyridine therapy did not significantly increase the bleeding (OR: 0.95, 95% CI 0.79 to 1.14; P = .58). In these patients with CKD following PCI, prolonged thienopyridine therapy compared with short-term therapy, was associated with reduced all-cause mortality and stent thrombosis, without any significant difference in myocardial infarction, stroke, and bleeding. Thienopyridine prolongation decisions for CKD patients should be individualized after careful consideration of the benefit–risk balance.     

Dual-Antithrombotic Therapy With DOACs After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Atrial Fibrillation: A Meta-analysis of Randomized Controlled Trials

BackgroundThe choice of antithrombotic therapy for atrial fibrillation (AF) patients who have an acute coronary syndrome (ACS) or have undergone percutaneous coronary intervention (PCI) is challenging. We aimed to assess outcomes between dual-antithrombotic therapy with the use of direct-acting oral anticoagulants (DOACs) plus an antiplatelet agent (dual therapy) compared with warfarin plus 2 antiplatelet agents (triple therapy) for AF patients after PCI or with ACS.MethodsSystematic searches of multiple major databases were performed from their inception through September 2019. We included only randomized controlled trials. Odds ratios (ORs) were pooled with the use of a random-effects model.ResultsWe identified 4 randomized controlled trials, which included 7168 patients. Compared with triple-antithrombotic therapy with warfarin, dual-antithrombotic therapy with DOACs was associated with a significant reduction in major bleeding (OR 0.56, 95% confidence interval [CI] 0.38-0.82; P = 0.003) as well as major bleeding or clinically relevant nonmajor bleeding (OR 0.53, 95% CI 0.38-0.75; P < 0.001). The rate of composite of death and ischemic events (stroke and myocardial infarction) was not statistically different between groups (OR 1.21, 95% CI 0.99-1.49; P = 0.06). There was no significant difference between groups in the rate of death (OR 1.20, 95% CI 0.95-1.53; P = 0.13).ConclusionsIn patients with AF and recent ACS or PCI, the use of dual-antithrombotic therapy with DOACs was associated with less major bleeding and less major bleeding or clinically relevant nonmajor bleeding compared with triple therapy. The use of dual therapy also showed nonsignificantly higher composite of death and ischemic events but no difference in mortality.     

Dual Antiplatelet Therapy and Outcomes in Patients With Atrial Fibrillation and Acute Coronary Syndromes Managed Medically Without Revascularization: Insights From the TRILOGY ACS Trial

Associations between atrial fibrillation (AF), outcomes, and response to antiplatelet therapies in patients with acute coronary syndrome (ACS) managed medically without revascularization remain uncertain. We examined these associations for medically managed ACS patients randomized to dual antiplatelet therapy (DAPT) using patient data from the TRILOGY ACS trial. DAPT included aspirin plus clopidogrel 75 mg/d or prasugrel 10 mg/d (5 mg/d for those <60 kg or age ≥75 years). Patients receiving oral anticoagulants were excluded. Cox proportional hazards regression modeling was used to characterize associations between patients with AF (AF+) vs those without (AF?) and risk of ischemic and bleeding events, and to explore effects of randomized treatment on outcomes. Among 9101 patients with baseline AF status, 710 (7.8%) had AF. AF+ patients were older and had more comorbidities. Unadjusted associations of the composite of cardiovascular death/myocardial infarction/stroke were significantly higher among AF patients at 30 months (31.1% vs 18.4%; HR: 1.61, 95% CI: 1.35‐1.92, P < 0.001), but differences did not persist after adjustment (HR: 1.16, 95% CI: 0.97‐1.39, P = 0.11). When individual components of the composite endpoint were evaluated, 30‐month risk of events in AF+ patients was significantly higher. Thirty‐month risk of all‐cause death was significantly higher in AF+ patients: 18.1% vs 11.1% (HR: 1.62, 95% CI: 1.30‐2.02, P < 0.001). There was no significant interaction with randomized treatment and AF for the primary endpoint. Among medically managed high‐risk ACS patients receiving DAPT, AF was associated with higher unadjusted risks of ischemic and bleeding outcomes that were similar by treatment group.     

Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial.

OBJECTIVES: The purpose of this study was to determine the possible benefit of dual antiplatelet therapy in patients with prior myocardial infarction (MI), ischemic stroke, or symptomatic peripheral arterial disease (PAD). BACKGROUND: Dual antiplatelet therapy with clopidogrel plus aspirin has been validated in the settings of acute coronary syndromes and coronary stenting. The value of this combination was recently evaluated in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, where no statistically significant benefit was found in the overall broad population of stable patients studied. METHODS: We identified the subgroup in the CHARISMA trial who were enrolled with documented prior MI, ischemic stroke, or symptomatic PAD. RESULTS: A total of 9,478 patients met the inclusion criteria for this analysis. The median duration of follow-up was 27.6 months. The rate of cardiovascular death, MI, or stroke was significantly lower in the clopidogrel plus aspirin arm than in the placebo plus aspirin arm: 7.3% versus 8.8% (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.72 to 0.96, p = 0.01). Additionally, hospitalizations for ischemia were significantly decreased, 11.4% versus 13.2% (HR 0.86, 95% CI 0.76 to 0.96, p = 0.008). There was no significant difference in the rate of severe bleeding: 1.7% versus 1.5% (HR 1.12, 95% CI 0.81 to 1.53, p = 0.50); moderate bleeding was significantly increased: 2.0% versus 1.3% (HR 1.60, 95% CI 1.16 to 2.20, p = 0.004). CONCLUSIONS: In this analysis of the CHARISMA trial, the large number of patients with documented prior MI, ischemic stroke, or symptomatic PAD appeared to derive significant benefit from dual antiplatelet therapy with clopidogrel plus aspirin. Such patients may benefit from intensification of antithrombotic therapy beyond aspirin alone, a concept that future trials will need to validate. (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [CHARISMA]; http://clinicaltrials.gov/ct/show/NCT00050817?order=1; NCT00050817).     

Efficacy and safety of bivalirudin in patients receiving clopidogrel therapy after diagnostic angiography for percutaneous coronary intervention in acute coronary syndromes

Objectives : This study sought to investigate if the efficacy of bivalirudin monotherapy is similar to heparin plus GP IIb/IIIa inhibition in patients with acute coronary syndromes (ACS) treated with clopidogrel following diagnostic angiography. Background : Prior trials have demonstrated that peri‐procedural bivalirudin therapy confers similar efficacy as heparin plus GP IIb/IIIa inhibitors, while lowering the risk of bleeding complications in ACS patients undergoing percutaneous coronary intervnetions (PCI). However, the incidence of adverse ischemic events post‐PCI appeared to be higher in patients receiving bivalirudin without adequate pretreatment with clopidogrel. Methods : Using the 2004/2005 Cornell Angioplasty Registry, we evaluated 980 consecutive patients undergoing urgent PCI for UA/NSTEMI who were treated with either bivalirudin or UFH plus GP IIb/IIIa inhibitor. We excluded patients who were on chronic clopidogrel therapy or received clopidogrel pretreatment prior to angiography. All patients received a clopidogrel load (≥300‐mg dose) immediately before or after the PCI. Long‐term all‐cause mortality was obtained for 100% of patients, with a mean follow‐up of 24.6 ± 7.7 months. Results : Of the 980 study patients, 461 (47.0%) were treated with bivalirudin and 519 (53.0%) patients received UFH plus GP IIb/IIIa inhibitor. DES were used in 88% of PCI; 45% of patients presented with NSTEMI. The incidence of in‐hospital death (0.4% vs. 0.2%, P = 0.604), post‐procedural MI (6.9% vs. 5.4%, P = 0.351), and MACE including death, stroke, emergent CABG/PCI, and MI (7.6% vs. 5.8%, P = 0.304) were similar in patients treated with bivalirudin versus UFH plus GP IIb/IIIa inhibitors, respectively. The incidence of in‐hospital stent thrombosis was similar (0.7% vs. 0%, P = 0.104), while major (0.9% vs. 2.9%, P = 0.034) and minor bleeding (10.4% vs. 18.9%, P < 0.001) was reduced in the bivalirudin‐treated group. By two‐years of follow‐up, after propensity‐score adjusted multivariate Cox regression analysis, there was no significant difference in long‐term mortality between the two groups (HR 1.18; 95%CI 0.64–2.19, P = 0.598). Conclusions : In patients presenting with ACS and receiving clopidogrel treatment after angiography (before or within 30 min of PCI), peri‐procedural bivalirudin monotherapy suppresses acute and long‐term adverse events to a similar extent as does UFH plus GP IIb/IIIa inhibitors, while significantly lowering the risk of bleeding complications. © 2010 Wiley‐Liss, Inc.     

Comparison of platelet P2Y(12) ADP receptor-mediated pathway inhibition in triple versus dual antiplatelet therapy as assessed by VASP-phosphorylation in Japanese patients undergoing coronary stenting

Despite wide interindividual variability in response to clopidogrel, platelet P2Y(12) ADP receptor inhibition in Japanese patients has not been fully studied using specific methodology. This study compared platelet P2Y(12) ADP receptor inhibition during treatment with clopidogrel versus clopidogrel plus cilostazol in patients undergoing coronary stenting. Forty-two patients in whom platelet function was measured within 2 months after coronary stenting were enrolled. All patients were treated with aspirin 100 or 200 mg/day, and were divided into a dual therapy group (aspirin plus clopidogrel 75 mg/day; n = 34) and a triple therapy group (aspirin plus clopidogrel 75 mg/day plus cilostazol 200 mg/day; n = 8). Vasodilator-stimulated phosphoprotein (VASP) phosphorylation analysis and 5 and 20 μmol/L-induced maximal platelet aggregation were assessed. No differences were found in baseline characteristics except for a higher incidence of diabetes mellitus (DM) in the triple therapy group. Although there were no differences in platelet aggregation between the 2 groups, VASP index was significantly lower in the triple therapy group than in the dual therapy group (23.1 ± 15.3% versus 51.2 ± 19.9%; P = 0.001). The rate of low responsiveness to clopidogrel, defined by VASP index > 50%, was lower in the triple therapy group than in the dual therapy group (12.5% versus 55.9%; P = 0.047). Similarly, in DM patients the triple therapy group had a lower VASP index compared with the dual therapy group (23.1 ± 15.3% versus 47.0 ± 23.5%; P = 0.015).Clopidogrel plus cilostazol is more effective in inhibiting the platelet P2Y(12) ADP receptor pathway than clopidogrel alone. This may be useful for reducing clopidogrel resistance in Japanese patients.     

Benefits and risks of clopidogrel pretreatment before coronary artery bypass grafting in patients with ST-elevation myocardial infarction treated with fibrinolytics in CLARITY-TIMI 28

The Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28) trial was a randomized, double-blind, placebo-controlled study of clopidogrel in 3,491 patients receiving fibrinolytic therapy for ST-segment elevation myocardial infarction. Patients were randomized to clopidogrel or placebo begun at the time of fibrinolysis. This analysis reports the outcomes among the 136 patients in the trial population who underwent coronary artery bypass grafting (CABG) during the index hospitalization. There was no difference in the rates of TIMI major or minor bleeding between the clopidogrel and placebo groups from randomization to the end of follow-up (13.6% vs. 14.3%, P = 1.0) or from the time of CABG to the end of follow-up (9.1% vs. 11.4%, P = 0.78). When any day for study medication discontinuation ≤5 days prior to CABG was chosen as a cut point to evaluate bleeding risk for clopidogrel vs. placebo, there was no excess bleeding in the clopidogrel group. Among patients undergoing CABG, there was a trend toward reduction in the risk of cardiovascular death, recurrent MI, or recurrent ischemia requiring urgent revascularization at 30 days for those taking clopidogrel (OR 0.66, 95% CI 0.27–1.5; P = 0.37), consistent with the benefit seen in the overall trial population (OR 0.80, CI 0.65–0.97; P = 0.03). In conclusion, early clopidogrel treatment among CLARITY-TIMI 28 patients undergoing CABG was not associated with an increase in the rate of peri-operative bleeding and showed a trend toward reduction in 30-day ischemic events.     

Dual versus triple antithrombotic therapy in patients undergoing percutaneous coronary intervention-meta-analysis and meta-regression

BackgroundAnti-thrombotic regimen in patients on long term anticoagulation requiring coronary intervention remains a clinical challenge.MethodsWe performed a meta-analysis of observational studies and randomized controlled trials comparing outcomes of triple therapy (dual antiplatelet therapy and anticoagulant) with dual therapy (P2Y12 inhibitor and anticoagulant) in patients on long-term anticoagulants after percutaneous coronary intervention (PCI). Major bleeding was the primary outcome.ResultsThree observational studies and 3 randomized controlled trials with a total of 6654 patients met our selection criteria. At a mean follow up of 12.5 months major bleeding was lower in dual therapy cohort compared to triple therapy (2.2% vs 5.2%, RR 0.60, 95% CI 0.44–0.81, P = 0.001). No difference was observed between the two groups for major adverse cardiac events (11.8% vs 13.0%, RR 1.03, CI 0.79–1.34, P = 0.85), all-cause mortality (3.9% vs 5.6%, RR 0.94, CI 0.65–1.36, P = 0.76), myocardial infarction (3.7% vs 3.9%, RR 1.12, CI 0.83–1.50, P = 0.47), target vessel revascularization (6.8% vs 7.1%, RR 1.12, CI 0.72–1.74, P = 0.60), thromboembolic events (1.3% vs 1.6%, RR 0.95, CI 0.55–1.64, P = 0.85) and stent thrombosis (1.3% vs 1.4%, RR1.36, CI 0.84–2.21, P = 0.21).ConclusionFor patients undergoing PCI and requiring long term anticoagulation, a strategy of P2Y12 inhibitor plus anticoagulant confers a benefit of less major bleeding with no difference in major adverse cardiac events, mortality, myocardial infarction, target vessel revascularization, stent thrombosis or thromboembolism compared with triple therapy.